Porous ceramic composite bone grafts

ABSTRACT

The invention relates to porous ceramic composites incorporating biodegradable polymers for use as a bone substitute in the fields of orthopaedics and dentistry or as a scaffold for tissue engineering applications. The porous ceramic composite implant for connective tissue replacement comprises a porous ceramic matrix having a biodegradable polymer provided on internal and external surfaces of the ceramic matrix. The biodegradable polymer allows for the passage and/or delivery of a variety of agents throughout the porous ceramic matrix and improves mechanical properties of the implant in vivo.

FIELD OF THE INVENTION

This invention relates to porous ceramic composites incorporatingbiodegradable polymers for use as a bone substitute in the fields oforthopedics and dentistry or as a scaffold for tissue engineeringapplications. The invention further relates to methods for producingsuch composites alone or in combination with pharmaceutical agents.

BACKGROUND OF THE INVENTION

Currently, the most common practice for replacing damaged or diseasedbone is to use autograft (bone removed from the patient). However, highincidences of donor site morbidity, the necessity of a painful second‘harvesting’ surgical procedure, and the absence of large quantities ofbone available for grafting compromises patient outcomes. Concerns withallografts (bone taken from a cadaver) and xenografts (bone obtainedfrom animals) include: (1) transmission of disease, (2) difficulty ofprocurement and processing, (3) uncertain immune response, and (4)premature resorption.

As a consequence of the limitations associated with ‘natural’ grafts,there is significant advantage for the development of synthetic bonegrafts that have the potential to offer important advantages, including:elimination of the risk of disease transmission; reduced occurrence ofan adverse immunological response; absence of painful ‘harvesting’procedure; relatively low costs; unlimited supply; and the ability toincorporate pharmaceutical agents that accelerate the bone healingprocess.

As the main inorganic component of bone consists of a highly substitutedcalcium phosphate (CaP) apatite, researchers concerned with developingsynthetic bone substitutes have concentrated on the various forms ofCaP. These include hydroxyapatite, carbonated apatite, fluroapatite, αand β tricalcium phosphate, tetracalcium phosphate, octacalciumphosphate, and combinations thereof. In general, these materials haveproven to be both biocompatible and osteoconductive and are welltolerated by host tissues. However, to be an effective bone substitute,these materials must possess the appropriate physical structure andmechanical properties. Of particular concern, structurally, is the levelof porosity, pore size, and size of the interconnections between eachpore.

Currently commercially available synthetic bone grafts possess lowlevels of porosity, inappropriate pore size and pore size distribution,and inadequate pore connectivity to permit vascularization of theimplant and, thus, do not adequately support tissue in-growth. Anotherdisadvantage of commercially available bone grafts is their poormechanical properties, which limits the use of these implants tonon-load bearing applications. Furthermore, the techniques used tomanufacture these implants do not permit the production of porous bodieswith gradient porosity or those with a solid cortical shell; necessaryproperties for applications involving segmental defects.

Mechanical fixation of orthopedic implants can lead to the unintentionalrelease of particulate debris that can migrate into surrounding tissuesor articular joints. The presence of this debris can compromise thevitality of surrounding tissues or damage articular surfaces, leading tobone resorption, osteolysis and the failure of such implants over time.As such, another major disadvantages of commercially available syntheticbone grafts is the risk of particulate debris generation and migrationarising from the use of standard orthopedic fixation techniques.

There are several patents describing methods of producing porous bodiesfor use as bone replacements; see for example, U.S. Pat. Nos. 3,899,556,3,929,971, 4,654,314, 4,629,464, 4,737,411, 4,371,484, 5,282,861,5,766,618, 5,863,984, WO 95/32008 and WO99119003. A common technique forproducing porous ceramic bodies involves the use of pore forming agentsas described in U.S. Pat. Nos. 4,629,464, 4,654,314, 3,899,556 and WO95/32008. Pore forming agents, however, typically result in a ‘closedcell’ structure characterized by inadequate pore interconnectivity. Itis well known that tissue in-growth into porous materials is a functionof both pore size and pore connectivity. Many researchers have attemptedto overcome this lack of pore connectivity by increasing the fraction ofpore forming agents used and, whilst this does slightly improve poreconnectivity, the accompanying loss of mechanical strength makes theresulting structure impractical for clinical use.

U.S. Pat. No. 4,737,411 discloses a method for producing porousceramics. In this method, a ceramic composite having an open porousnetwork and a controlled pore size is produced by coating ceramicparticles, of known size, with a glass coating. These coated ceramicparticles were subsequently pressed into the desired shape and sinteredsuch that the glass coating fused the ceramic particles together.Through the close control of the particle size and thickness of theglass coating, the size of the pores formed between the fused particlescould be controlled. This technique of forming porous ceramics for bonereplacement is somewhat limited, as the maximum pore size obtainable isapproximately 150 μm, whilst previous research has shown that pore sizesup to 500 μm are required for optimum tissue in-growth.

U.S. Pat. No. 3,299,971 discloses a method of producing a poroussynthetic material for use in hard tissue replacement. In this method, aporous carbonate skeletal material of marine life (coral) is convertedinto a porous hydroxyapatite material through a hydrothermal chemicalexchange with a phosphate. The final microstructure of the convertedhydroxyapatite material is essentially the same as that of the coralfrom which it was formed. Consequently, pore size is dependent on thetype of coral used. While these porous structures possess theappropriate pore size and pore connectivity for hard tissue in-growth,the structure is limited to that of the selected coral and so theproduction of implants with a solid shell surrounding the porous network(typical of cortical or long bone, for example) is unobtainable. Inaddition, the bone grafts manufactured using this technique arecharacterized by poor mechanical properties and are difficult to handleand shape and cannot be secured using standard fixation techniques.

Reticulated foams made from an organic material, such as polyurethane,are characterized by pore interconnectivity, high porosity, and areavailable in a variety of pore sizes. As such, these reticulatedstructures have been used to manufacture porous bodies of metal orceramic composition. While typically used in molten metal filtrationapplications, both ceramic and metal foams manufactured from the coatingof reticulated polyurethane networks have found increasing use inorthopaedic and dentistry applications. For example, U.S. Pat. No.5,282,861 discloses a reticulated carbon foam (converted frompolyurethane using a thermal treatment) that was used to manufacture anopen cell tantalum foam for use as an implant in both hard and softtissue. Tantalum was applied to the surface of the carbon foam as a thinfilm using a chemical vapour deposition (CVD) technique. As such, theTantalum-coated foam replicated closely the morphology of thereticulated carbon foam substrate. While Tantalum is biocompatible (i.e.inert), it is non-degradable and non-resorbable and, as such, will beimplanted permanently. This is also the case with total hip and kneereplacements and, while the titanium and cobalt alloys used to fabricatethese implants are also considered to be ‘biocompatible’, long-termimplantation of these devices often results in adverse systemic effectssuch as metal ion sensitization. As a consequence of these problems, itis becoming increasingly desirable to use, where possible, an implantthat will eventually be resorbed and replaced with natural, healthy bonytissue.

U.S. Pat. No. 3,946,039 discloses a method to produce porous ceramic ormetal structures using reticulated polyurethane foam. In this method areticulated polyurethane foam is invested with an inorganic compositionthat is not compromised by the processing conditions required forforming the reticulated ceramic or metal structure. The polyurethanefoam structure is removed using a chemical or thermal process, and thevoids remaining in the investment are filled with a fluid composition(metal or ceramic) to form a reticulated casting. The final step of thisprocess involves dissolving the investment so as to leave thereticulated ceramic or metal foam structure casting. The disadvantagesof this technique are similar to that of the coral conversion method inthat the structure of the final part is limited to the structure of thestarting foam. Furthermore, the incorporation of a solid outer shell ordensity gradients is difficult or unobtainable.

Perhaps the most common technique for producing porous bodies fromreticulated polyurethane foam is a replication technique, as disclosedin U.S. Pat. Nos. 4,371,484, 6,136,029, 3,947,363, 4,568,595, 3,962,081,4,004,933, 3,907,579, 5,456,833 and WO 95/32008. In general, thistechnique involves impregnating a reticulated polyurethane foamstructure with a metal or ceramic slurry to deposit a thin film ofcoating material onto the surface of the foam substrate. Excess slurryis commonly removed from the pores by passing the foam through a set ofrollers, centrifuging, or blasting with a jet of air. After the excessslurry has been removed, the reticulated structure is dried and theorganic foam substrate removed by pyrolysis. This typically involvesheating to temperatures between 200° C. and 500° C. After the pyrolysisof the foam substrate, the temperature is increased for the subsequentsintering of the metallic or ceramic particles.

U.S. Pat. Nos. 5,456,833 and 4,568,595 describe two different methodsfor forming a solid shell of material around a coated reticulatedstructure. The former describes the use of a pressed annular ring arounda reticulated cylinder while the latter indicates the use of a secondaryprocess where a high viscosity slurry is applied to the outside of thereticulated structure to generate a solid coating following thermalprocessing in order to improve the strength of the reticulatedstructure.

U.S. Pat. No. 6,136,029 discloses a method to produce a porous structuresuitable for bone substitution comprising a continuous, strong,framework structure of alumina or zirconia using the standardreplication technique. In an attempt to provide osteoconductive and/orosteoinductive properties to the porous implant, a second material ofosteoconductive/osteoinductive composition was included. The secondmaterial could be present in several forms, including (1) a coating onthe surface of the framework structure, (2) in the form of a composite,intimately mixed with the framework material, or (3) as a porous masswithin the interstices of the framework structure. The second phasematerials outlined as being suitable for this invention includedosteoconductive materials such as collagen and the various forms ofcalcium phosphate (hydroxyapatite, tricalcium phosphate, etc.) andosteoinductive materials such as bone morphogenetic proteins (BMP's),demineralized bone matrix, and transforming growth factors (TGF-β). Thevariations to the foam replication process as outlined in this patentare important in bone substitution applications as they provide a meansto produce a composite implant capable of delivering pharmaceuticalagents that may enhance the rate of healing. However, the use of aninert framework structure as a means of providing the implant withimproved mechanical properties severely limits the use of this devicefor hard tissue replacement. As previously mentioned, it is desirablethat the implanted material be completely replaced with natural bonytissue.

As the repair or replacement of bony voids or defects is site specific,pharmaceutical agents, such as bone growth factors, must be locallydelivered via an appropriate carrier. Biodegradable polymers have beenused as drug delivery vehicles as they can be implanted directly at thesite of repair and their rate of degradation and, hence, rate of drugdelivery can be controlled. However, such biodegradable polymers do notpossess the mechanical properties suitable for hard tissue replacement.As such, there has been an increased interest in polymeric/ceramiccomposites, as disclosed for example U.S. Pat. No. 5,766,618 and WO99/19003.

U.S. Pat. No. 5,766,618 describes a method of forming a polymer/ceramiccomposite in which a biocompatible and biodegradable polymer (PLGA) wascombined with a calcium phosphate ceramic (hydroxyapatite) in an attemptto improve the mechanical properties of the polymer matrix. While theincorporation of a ceramic phase provided an initial improvement inelastic modulus, immersion of the implant in a simulated physiologicalenvironment resulted in a rapid decrease in modulus from 1459 MPa toless than 10 MPa in under six weeks. Clearly, such rapid degradation ofmechanical properties limits the use of this device for hard tissuereplacement applications.

WO 99/19003 describes an injectable polymer/ceramic gel that is fluidunder non-physiological conditions and non fluid under physiologicalconditions. Composed of natural or synthetic, resorbable ornon-resorbable polymers mixed with a ceramic phase, the gel is limitedto filling very small bony defects and does not possess the mechanicalproperties or porous structure for the treatment of large segmentaldefects.

It is apparent from the aforementioned prior art that a variety ofmethods have been developed to manufacture porous implants suitable forbone repair and/or replacement. However, current methods and implantspossess several shortcomings that make the resultant function of theimplant less than satisfactory for prolonged implantation. It wouldtherefore be advantageous to develop a porous implant and method ofmaking such that obviates the shortcomings of the prior art.

The Applicant's U.S. Pat. No. 6,323,146 discloses a syntheticbiomaterial compound (Skelite™) composed of silicon-stabilized calciumphosphate. Extensive testing demonstrated that this compound is ideallysuited for use as a bone substitute material as it is: (1) 100%synthetic, (2) biocompatible, (3) able to participate in the body'snatural bone remodeling process, and (4) relatively inexpensive toproduce. U.S. Pat. No. 6,323,146 also describes a method of forming aporous body of the Skelite™ compound by replicating a reticulatedorganic foam substrate. It is now demonstrated that the syntheticbiomaterial compound can be incorporated with a biodegradable polymer insuch a manner to provide a variety of implants that possess sufficientmechanical strength to be used as a bone substitute in both load-bearingand non-load bearing applications and further overcomes thedisadvantages associated with implants of the prior art.

SUMMARY OF THE INVENTION

The present invention provides a porous bone substitute and method ofmaking thereof, that overcomes several of disadvantages of the prior artand meets many of the specifications outlined below.

-   -   1. Be fabricated from a material that does not invoke an adverse        immunological response.    -   2. Promote the rapid in-growth of new bony tissue.    -   3. Participate in the body's natural bone remodeling process and        be replaced by healthy tissue.    -   4. Possess an open, interconnected porous structure with the        appropriate pore size, pore size distribution, porosity, and        pore connectivity.    -   5. Be relatively inexpensive to produce and readily available.    -   6. Have the ability to deliver pharmaceutical agents, such as        bone growth factors, in a controllable manner.    -   7. Be able to be readily handled and shaped by the surgeon using        standard techniques.    -   8. Be able to be secured into place using standard orthopaedic        fixation techniques without generating particulate debris that        may migrate to articulating surfaces.    -   9. Be manufactured by a flexible process that permits gradient        porosity and/or a solid shell surrounding a portion of the        porous network, for example.

In accordance with the present invention there is provided a porous bonesubstitute that can limit fragmentation, and the subsequent migration ofparticulate debris, during standard orthopaedic fixation practice. Theporous bone substitute is a porous ceramic composite.

In accordance with the present invention, is a composite bone substitutecomprising a porous osteoinductive ceramic matrix and a biodegradablepolymer. In a preferred embodiment, the biodegradable polymer isprovided as a coating on the ceramic matrix. The osteoinductive porousceramic matrix possesses optimum pore size, pore size distribution,porosity, and pore connectivity to promote the rapid in-growth of bonytissue.

In aspects of the invention, the porous matrix has a porosity of about200 to about 600 microns.

According to an aspect of the present invention there is provided aporous ceramic composite implant, said implant comprising;

a porous ceramic matrix having a biodegradable polymer provided oninternal and external surfaces of said ceramic matrix, wherein saidbiodegradable polymer allows for the passage and/or delivery of avariety of agents throughout said porous ceramic matrix and improvesmechanical properties of said implant.

According to another aspect of the present invention is a porous ceramiccomposite comprising;

an isolated bioresorbable biomaterial compound comprising calcium,oxygen and phosphorous, wherein a portion of at least one of saidelements is substituted with an element having an ionic radius ofapproximately 0.1 to 0.6 A and a biodegradable polymer.

According to a further aspect of the present invention is a porousceramic composite comprising;

a biomaterial compound having the formula:(Ca)_(i)((P_(1-x-y-z)B_(x)C_(y)D_(z))O_(j)]₂

wherein B, C and D are selected from those elements having an ionicradius of approximately 0.1 to 0.4 Å;

x is greater than or equal to zero but less than 1;

y is greater than or equal to zero but less than 1;

z is greater than or equal to zero but less than 1;

x+y+z is greater than zero but less than 1;

j is greater than or equal to 2 but less than or equal to 4;

j is equal 4−δ, where δ is greater than or equal to zero but less thanor equal to 1; and

a biodegradable polymer.

According to a further aspect of the present invention, thebiodegradable polymer coating is porous in order that the underlyingosteoinductive ceramic matrix is exposed to the physiologicalenvironment and positively influence bone cell behaviour.

According to another aspect of the present invention, the polymer has asubstantially high degree of porosity. In aspects the porosity is about50 to about 200 microns.

According to a further aspect of the present invention, thebiodegradable polymer itself is a composite material containing smallquantities of the osteoinductive ceramic material such that cells incontact with the implant surface will be stimulated to initiate the bonerepair process.

According to a further aspect of the present invention, the pores of theosteoinductive ceramic matrix are filled with a porous network of abiodegradable polymer of a composition the same as, or different, thanthe polymer coating.

According to a further aspect of the present invention, the porousnetwork may be formed with a variety of polymers includingphotosensitive polymers. The photosensitive polymer is present during invivo or in cell seeding, proliferation and differentiation phases oftissue formation. The photosensitive polymer is subsequentlyphotosolubilized as the precursor to growth factor and/or cell inducedvascularization of the implant.

According to a further aspect of the present invention, the hollowligaments (struts) of the porous ceramic matrix are filled with abiodegradable polymer of a composition the same as, or different, thanthe polymer coating.

According to a further aspect of the present invention, theosteoinductive porous ceramic matrix is partially surrounded by a solidlayer of a composition the same as, or different, than the ceramicmatrix.

According to a further aspect of the present invention, the ceramicmatrix possesses a gradient density with the outermost regions of thestructure being the most dense and porosity increasing towards thecenter of the structure.

According to a further aspect of the present invention, thebiodegradable polymer coating acts as a carrier and permits controlledrelease of selected pharmaceutical agents such as, but not limited to,bone growth factors.

According to a further aspect of the present invention, thebiodegradable polymer coating acts as a carrier for living cells orgenes for use in cell and/or gene therapy applications. As thebiodegradable polymeric-coating degrades, cells or genes bound to orentrapped within the coating are released to the intended site ofdelivery.

According to a further aspect of the present invention, theosteoconductive porous ceramic matrix possesses more advantageousmechanical properties to those of the prior art as a result ofrepeatedly coating the organic substrate with slurries varying in solidsloading.

According to a further aspect of the present invention pore size, poresize distribution, porosity, and pore connectivity of the organic foamsubstrate is replicated in the sintered porous body by using a vacuum orcontrolled gas jet to remove any excess slurry trapped within the foamstructure.

According to a further aspect of the present invention, the slurry usedto impregnate the organic foam substrate is sufficiently milled toproduce a slurry with thixotropic rheological properties.

According to yet a further aspect of the present invention is a methodof making a porous ceramic implant for connective tissue replacement,said method comprising;

(i) impregnating an organic reticulated foam structure with a slurry ofcalcium-phosphate compound;

(ii) drying the impregnated foam structure to form a slurry coated foamstructure; and

(iii) pyrolyzing the slurry coated foam structure formed in (ii) andsintering to provide a fused ceramic porous implant having a pluralityof interconnected voids.

In alternative aspects, binders, wetting agents and antifoaming agentsare provided to the slurry prior to impregnation of the reticulated foamstructure. Furthermore, in other aspects, the organic reticulated foamstructures exhibit a gradient porosity.

In any of these aspects, the porous ceramic implant may be coated with asuitable biodegradable polymer such as but not limited topolycaprolactone (PCL). In further aspects of the invention, thebiodegradable polymer may be manufactured as a composite containingparticles of the porous ceramic.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating embodiments of the invention are given by wayof illustration only, since various changes and modifications within thespirit and scope of the invention will become apparent to those skilledin the art from said detailed description.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is directed to the manufacture and use of a porous ceramiccomposite comprising a sintered porous matrix body of a calciumphosphate-based compound and a biodegradable polymer. It is nowsurprisingly and advantageously demonstrated that the calcium-phosphatebased compound described in applicant's U.S. Pat. No. 6,323,146 (thecontents of which are herein incorporated by reference) can be used inconjunction with a biodegradable polymer to form a porous ceramiccomposite implant for both non-load bearing and load bearing in vitroand in vivo applications.

The porous ceramic composite implant of the present invention may beused generally for connective tissue replacement. The polymer allows forthe passage and/or delivery of a variety of agents throughout the porousceramic matrix which helps to provide optimum tissue in-growth.Furthermore, the biodegradable polymer coating helps to improvefunctional (mechanical) properties of the implant in vivo. Preferably,the porous ceramic matrix is formed from the Applicant'scalcium-phosphate compound described in U.S. Pat. No. 6,323,146 (thedisclosure of which is herein incorporated by reference in itsentirety). In various aspects, the biodegradable polymer is provided asa continuous or discontinuous coating on the inner and outer surfaces(i.e. throughout) of the porous ceramic matrix. In another aspect, thepolymer coating may also be porous and provided as a continuous ordiscontinuous coating throughout the porous ceramic matrix. In a furtheraspect, the polymer coating may have ceramic particles incorporatedtherein to form a polymer composite material. The ceramic particles arepreferably sintered particles of the Applicant's calcium-phosphatecompound described in U.S. Pat. No. 6,323,146. Alternatively, theceramic particles may be made from a variety of calcium phosphatematerials selected from the group consisting of hydroxyapatite,carbonated apatite, fluroapatite, a tricalcium phosphate, β, tricalciumphosphate, tetracalcium phosphate, octacalcium phosphate and mixturesthereof. It is also within the scope of the present invention to providea coating (continuous or discontinuous) of biodegradable polymer that isboth porous and contains ceramic particles.

In one embodiment of the invention, a porous ceramix matrix body isformed from an organic reticulated foam structure having a plurality ofinterconnected voids. These structures are commercially available or canbe prepared, if desired. The foam structure is impregnated with anaqueous slurry such that the ligaments (struts) of the foam are coatedand the voids are substantially filled. The excess slurry is removedfrom the pores and the coated structure is dried forming what istypically called a green body (i.e. unsintered coated foam structure).Drying make take from a few minutes to over an hour as is understood bythose of skill in the art. This process is repeated until the coating ofslurry attains the desired thickness throughout the foam structure.Typical thickness of coating may be about 10 to about 100 microns. Thecoated structure is then heated to first burn out the flexible organicfoam and then sintered, thereby providing a fused ceramic foam having aplurality of interconnected voids. Heating is typically done attemperatures of about 25° C. up to about 200° C. Sintering is typicallyconduced at temperatures of about 900° C. to about 1300° C. The heatingand sintering is done in succession such that the temperature is rampedup to the sintering temperatures.

It is desirable that the aqueous slurry used to form the porous ceramicmatrix be composed of an osteoconductive or osteoinductive material thatis biocompatible and actively participates in the body's natural boneremodeling process. In a preferred embodiment, the biocompatiblematerial is Skelite™, an isolated bioresorbable biomaterial compoundcomprising calcium, oxygen and phosphorous, wherein a portion of atleast one of said elements is substituted with an element having anionic radius of approximately 0.1 to 0.6 Å. Specifically, thisbiomaterial compound has the formula:(Ca)_(i){(P_(1-x-y-z)B_(x)C_(y)D_(z))O_(j)}₂

wherein B, C and D are selected from those elements having an ionicradius of approximately 0.1 to 0.4 Å;

x is greater than or equal to zero but less than 1;

y is greater than or equal to zero but less than 1;

z is greater than or equal to zero but less than 1;

x+y+z is greater than zero but less than 1;

i is greater than or equal to 2 but less than or equal to 4; and

j is equal 4−δ, where δ is greater than or equal to zero but less thanor equal to 1.

Preparation of the slurry involves combining the ceramic material with afluid medium, typically water, and a dispersing agent. Dispersing agentsmay be used to prevent agglomeration of the ceramic particles and can beeither organic or inorganic. Examples of organic dispersants includesodium polyacrylate, ammonium polyacrylate, sodium citrate, sodiumtartrate and mixtures thereof. Examples of inorganic dispersantsinclude, sodium carbonate, sodium silicate, tetrasodium pyrophosphateand mixtures thereof. The quantity of dispersing agent added istypically but not limited to between about 1 and 3.5 Vol %.

It has been found that the initial particle size of the ceramic materialplays a role in the strength of the final product. In addition, particlesize significantly influences both the solid loading capability and theresulting viscosity of the slurry. Milling a portion of the slurry hasbeen found to be useful in obtaining the desired particle sizedistribution. Typically, a portion of the slurry is milled between 1 and24 hrs using an inert, abrasive-resistant milling media such as aluminaor zirconia to provide ceramic particles of about up to 50 microns (andany size or ranges in size up to about 50 microns). In order for theceramic particles of the slurry to adhere to both the foam substrate andto each other, it is desirable that, after particle size reduction, theslurry is thixotropic in nature. That is, viscosity of the slurry isreduced under increasing rates of shear.

Prior to impregnating the reticulated foam body, additives may also beadded to the slurry. These may include a binder, to impart strength tothe green body, a wetting agent, to improve distribution of the slurrythroughout the foam, and an antifoaming agent that reduces the formationof bubbles in the slurry. These components are added to the slurry insmall amounts, typically but not limited to less than about 10 vol % forthe binder and less than about 2 vol % for the wetting and antifoamingagents.

It has been found that good compressive strength, about 10 MPa, can beachieved by applying several coats and drying the impregnated structurebetween each coating. While the porous structure of the foam may beginto become clogged as the latter coats are applied, it has been foundthat using a slurry with a high solids loading (up to about 30 Vol %)for the first several coats, followed by several coats with a slurrypossessing a lower solids loading (below about 20 Vol %) helps to avoidany clogging.

In the present invention, an effective method of removing the excessslurry is to use a vacuum process. In this case, the impregnated foam isplaced onto a mesh screen fitted to the top of a vertically mountedvacuum hose and the excess slurry is drawn through the hose into thevacuum unit. Alternately, a controlled gas jet can be used to disperseexcess slurry that occludes internal pores.

To remove the organic reticulated foam structure, the dried coatedstructure is transferred to an electric furnace and heated to and heldat a temperature sufficiently high (i.e. up to about 200° C.) topyrolyze the underlying polymer foam. Subsequent sintering of theceramic structure (at temperatures of up to about 1300° C., morepreferably about 1000° C. to about 1300° C.) is performed by heating toa temperature significantly higher than the temperature used to pyrolyzethe foam. The furnace is then allowed to cool to room temperature.

A porous structure exhibiting gradient porosity can be manufactured byusing centripetal force to distribute the slurry to the outer surface ofthe reticulated structure. This can be accomplished by rotating acylindrical reticulated foam body inside a tube whose interior is linedwith an absorbent material. A hollow channel down the center of thereticulated foam body permits a nozzle to travel along the long axis ofthe reticulated cylindrical part. Slurry is fed through the nozzle asthe tube is rotated. Beginning at the far end of the reticulated part,the nozzle travels the length of the tube, via a linear drive, coatingthe spinning reticulated foam structure. The absorbent material securedto the inner surface of the tube dewaters the adjoining slurry and sopermits the accumulation of slurry at the outer surface of thereticulated cylinder. A porous ceramic body exhibiting gradient porosityis produced by repeating this process while altering importantprocessing variables such as tube rotational speed, slurry spraypressure, nozzle travel speed, and slurry solids loading.

In an alternative embodiment for producing a porous implant withgradient porosity, the foam is modified so that it possesses a gradientporosity prior to replication. This can be accomplished by coating thefoam in an appropriate thermally decomposable material, such as wax, andcentrifuging the wax-coated foam to force the molten wax to the outersurfaces of the foam. Gradient porosity can be accomplished by repeatingthis process several times. Once the desired gradient porosity isattained, the foam structure can be replicated using the standardreplication technique previously described.

In yet another further embodiment of producing a porous implant withgradient porosity, the polymer foam is preformed by physical distortioncombined with the application of heat or physical restraint to retainthe distorted shape throughout the ceramic replication process. Thedistorted shape can be configured to provide a continuous gradient orselected steps in pore size and pore geometry.

In a further embodiment of the present invention, and prior to theprovision of any biodegrable polymer, a solid outer layer partiallysurrounding the porous ceramic body may be formed by filling theinterstices of the sintered porous body with a thermally or chemicallydecomposable material, such as wax or calcium sulfate, and using a slipcasting process to coat selected surfaces with a solid ceramic coating.If a thermally decomposable material such as wax is used to fill theinterstices of the porous body, thermal processing will serve to meltand pyrolyze the wax followed by sintering of the dense exterior shell.This provides an implant that is similar to cortical or long bone.

The present invention provides a porous bone substitute (i.e. porousceramic matrix) that minimizes fragmentation, and the subsequentmigration of particulate debris, during standard orthopedic fixationpractice. The porous ceramic matrix can be made of various sizes,shapes, porosity, degree and sizes of porosity and including differentgradient porosities. This is particularly important for implantapplications occurring in close proximity to articular surfaces and isfurther accomplished by applying a biodegradable polymeric coating tothe surfaces of the porous ceramic matrix.

In order to form a porous ceramic compositie the porous ceramic matrixis further provided with a biodegradable polymer. A method of applying abiodegradable coating to the above described porous ceramic matrix (bodyor structure) first involves selecting a polymer that possesses theappropriate mechanical and degradation properties. Suitable polymers areknown to those of skill in the art. Once such a polymer has beenselected, it is dissolved in an appropriate solvent. The porous ceramicmatrix is placed into a mold and the polymer/solvent solution (typicallyabout 5-15% by weight polymer in solvent solution) is allowed toinfiltrate the interstices and encapsulate the outer surfaces of theporous ceramic body. The mold is placed under reduced pressure and thesolvent is allowed to evaporate until a polymer coating of a desiredthickness (about up to 250 microns and any range or ranges thereof) isapplied to both the external and internal surfaces of the porous ceramicmatrix. It is understood to those of skill in the art that thebiodegradable polymer coating can be provided on the porous ceramicmatrix as a continuous or discontinuous coating.

As is understood by one of skill in the art, a variety of biodegradablepolymers may be used in the practice of the invention. Such polymersinclude but are not limited to photosensitive polymers;polyhydroxybutyrate (PHB) and polyhydroxyvalerate (PHV) and copolymersthereof; polycaprolactone (PCL); polyanhydrides; poly (ortho esters);poly (amino acids) and psuedo-poly (amino acids); polyethylene glycol(PEG); and, polyesters such as poly(lactic acid) (PLA) and poly(glycolicacid) (PGA) and copolymers thereof. It is also understood by one skilledin the art that the different types of polymers and copolymers may becombined for use.

The above described method is advantageous due to the fact that polymercoatings can be applied at ambient temperatures, thus permitting theincorporation of pharmaceutical agents, such as but not limited to bonegrowth factors, into the polymer coating. Through proper selection ofthe polymeric material, an appropriate dose release profile may beachieved. Suitable pharmaceutical agents may include but are not limitedto antimicrobials, antibiotics (i.e. Tobramycin), epidermal growthfactor, fibroblast growth factor, platelet derived growth factor,transforming growth factor, parathyroid hormone, leukemia inhibitoryfactor, insulin-like growth factor, bone morphogenetic protein,osteogenin, sodium fluoride, estrogens, calcitonin, biphosphonates,calcium carbonate, prostaglandins, vitamin K and mixtures thereof.

In a further embodiment of the present invention, the biodegradablepolymer coating of the present invention may be made to be porousthrough the use of an appropriate pore forming agent. In still a furtherembodiment, the biodegradable coating, whether porous or not, may bemade to be a composite coating by adding discrete particles of a ceramicphase. In this aspect, ceramic particles are added into thepolymer/solvent solution prior to coating.

As the thickness of the polymeric coating may be varied and controlled,a preferred embodiment is the formation of a continuous porousbiodegradable polymeric phase throughout the interstices of the porousceramic matrix and is readily fabricated through the use of pore formingagents and extended immersion times.

One advantage of the present invention involving the replicationtechnique is that the ligaments (struts that compose the web of theceramic body) of the final structure are hollow. This provides a meansto improve the toughness of the porous ceramic body by filling thesechannels with an appropriate polymer. This can readily be achieved byinfusing the entire ceramic body with a polymer solution, including thehollow ligaments. This process is aided by the infusion of the polymerwhile the ceramic body is under vacuum, as the presence of the vacuumeliminates the potential for entrapped air within the hollow ligaments.Once the entire structure contains the desired polymer, the excesspolymer within the open voids is removed via vacuum or controlled gasjet. This then leaves the hollow ligaments filled with the polymer toimpart increased toughness and limiting the potential for fragmentationat the time of surgical implantation.

In summary, the present invention provides a porous bone substitute(“implant”) that has numerous advantages and uses in the field oforthopedics and dentistry both in vitro and in vivo. As an implant, theporous bone substitute can be used in both non-load bearing andload-bearing applications. The present invention also has use in celltherapy applications for the repair and/or regeneration of patienttissue by introducing the appropriate living cells within the microporesof the porous implant. Some candidate cells may include for example,cartilage cells, tendon cells, bone cells, ligament cells, organ cells,musculotendinous cells and mixtures thereof. Teeth or portions thereofmay also be incorporated within the porous ceramic matrix. The presentinvention also has use in gene therapy applications where the porousbone substitute can be used as a delivery device for genetically alteredcells to produce a desired biological agent at a desired site.

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific examples. These examples are described solely for purposes ofillustration and are not intended to limit the scope of the invention.Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

EXAMPLES

The examples are described for the purposes of illustration and are notintended to limit the scope of the invention.

Methods of chemistry and general processing methods for the ceramicsreferred to but not explicitly described in this disclosure and examplesare reported in the scientific literature and are well known to thoseskilled in the art.

Example 1 Preparation of Polymer-Coated Porous Ceramic Body

An open pore polyurethane foam with dimensions 12 mm×24 mm×60 mm wasprovided. Two aqueous ceramic slurries were provided. One slurry had a25 vol % solids loading and the other a 17 vol % solids loading. Bothslurries had been ball milled for 5 hrs and were thixotropic in nature.The foam material was immersed into the 25 vol % solids slurry andagitated to remove air, to substantially fill the voids with the slurry,and to coat the ligaments (struts) of the foam with the slurry. Theresultant impregnated foam was removed from the slurry and placed onto amesh screen that was attached to a vertically mounted vacuum hose.Excess slurry was removed from the voids by turning on the vacuum unitfor 3-5 seconds. This was sufficient time to remove excess slurry fromthe voids of the foam without disrupting the slurry that was adhered tothe struts of the foam. The coated foam was oven dried at 90° C. for 15minutes. This entire process was repeated 1-2 more times with the 25 vol% solids slurry and 4-5 more times with the 17 vol % solids slurry.

The dried coated foam substrate was transferred to an electric furnacewhere it was heated at a rate of 1° C./min to a temperature of 500° C.to drive off water and to allow the polyurethane foam to pyrolyzewithout collapsing the ceramic scaffold. The foam was held at 500° C.for 4 hrs and was, subsequently, heated, at a rate of 1° C./min, to atemperature of 1175° C. This temperature was held for 1 hr to permit theceramic particles to sinter together thereby providing an open cellceramic foam possessing the physical morphology of the originalpolyurethane foam material. Subsequently, the furnace was cooled at arate of 36° C./min until a final temperature of 25° C. was achieved. Thefinal dimensions of the sintered ceramic foam were 10 mm×20 mm×50 mm.

A polymer solution was provided by dissolving 5 g of polycaprolactone(PCL) in 95 g of dichloromethane. The solution was stirred in a beakerfor approximately 15 hrs at 225 rpm to ensure that the PCL wascompletely dissolved. The sintered porous ceramic was then placed in aTeflon mold and infiltrated with the polymer solution. The moldcontaining the polymer impregnated sintered body was, subsequentlytransferred to a vacuum desiccator for 20 minutes. This process wasrepeated 4 more times using decreasing volumes/concentrations of PCLsolution each time. The polymer-coated scaffold was then dried for 15-20hrs in the desiccator resulting in a polymer reinforced ceramic bodyexhibiting improved fracture toughness.

Example 2 Preparation of Polymer-Coated Porous Ceramic Body with CeramicParticles

A polymer-coated porous ceramic body was produced as in example 1. Inthis case, ceramic particles of a composition the same as the sinteredporous body were included into the PCL/dichloromethane solution. Theseceramic particles had a mean particle size of 6 μm and had been calcinedat a temperature of 1000° C. for 1 hr. The polymer/dichloromethanesolution had a ceramics solid loading between 20-30 vol %. Applicationof the polymer/ceramic composite coating to the sintered porous ceramicwas carried out as in example 1. This resulted in the production of athin composite coating consisting of discrete particles of the ceramicmaterial distributed evenly throughout the polymer matrix.

Example 3 Preparation of Polymer-Coated Porous Ceramic Body with PoreForming Agents

A polymer-coated porous ceramic body was produced as in example 1. Inthis case, pore forming agents were included in thepolymer/dichloromethane solution. Examples of pore forming agentssuitable for this application include polymer or wax beads with meltingand vaporization temperatures lower than that of PCL. The pore formingagent was included into the PCL/dichloromethane solution at levelsbetween 30-40 vol %. The polymer coating was applied to the porousceramic body as described in example 1. The coated porous ceramic bodywas subsequently transferred to an oven and heated to a temperaturegreater than the melting point of the chosen pore forming agent butbelow the melting temperature of the PCL coating (64° C.). This thermaltreatment caused the pore forming agent to volatize and produced a thinporous polymer coating on both the internal and external surfaces of theporous ceramic body.

Example 4 Method for Production of a Porous Ceramic Body ExhibitingGradient Porosity

An open pore polyurethane foam cylinder measuring 50 mm in diameter and13 mm in length was provided. A hole measuring 25 mm OD was producedthrough the center of the foam cylinder using a 25 mm ID punch. Theresulting foam tube was placed inside an aluminum cylindrical shellmeasuring 55 mm ID and 150 mm in length that had been lined with anabsorbent material.

Two aqueous ceramic slurries were provided. One slurry had a 25 vol %solids loading and the other a 17 vol % solids loading. Both slurrieshad been ball milled for 5 hrs and were thixotropic in nature. Using aperistaltic pump, the 25 vol % solids slurry was pumped through a nozzlethat could be translated along the central axis of the aluminumcylindrical shell via a support mounted on an external linear drive. Thealuminum shell containing the polyurethane foam ring was rotated at aspeed of 375-700 rpm while the nozzle, dispensing a fine mist of slurry,traveled along the axis of the rotating assembly. This process wasrepeated 1-2 more times with the 25 vol % slurry and 4-5 more times withthe 17 vol % solids slurry such that the foam ring was substantiallycoated and a density gradient was established with the outer surfaces ofthe foam substrate being the most dense and porosity increasing towardsthe center of the part. The coated foam ring was subsequentlytransferred to an electric furnace and processed as described in example1 to produce a porous ceramic body exhibiting gradient porosity.

Example 5 Production of a Porous Ceramic Body Exhibiting GradientPorosity

A open pore polymeric foam precursor exhibiting gradient porosity wasmanufactured using rapid prototyping techniques such assterolithography, fused deposition modeling, and 3D printing. Thepolymeric component was subsequently processed into a porous ceramicbody exhibiting gradient porosity using the replication technique asdiscussed above.

Example 6 Production of a Porous Ceramic Body Exhibiting a SolidExterior Shell

A porous ceramic body with a solid exterior shell was produced byrepeatedly immersing an open pore polyurethane foam precursor into athixotropic slurry, removing the excess slurry with a vacuum, andsintering the green body at temperatures in excess of 1000° C. for aperiod greater than about 1 hr. The sintered porous ceramic body wassubsequently infiltrated with molten wax such that, after cooling, allof the pores of the sintered ceramic body were plugged with solid wax.The infiltrated piece was subsequently shaped into the desired finalshape and placed in a slip casting mold that was slightly larger thanthe infiltrated ceramic body. The mold was subsequently filled with aceramic slip and allowed to dry. The new green body was carefullyremoved from the mold and sintered at a temperature in excess of about1000° C. for a period of about 1 hr or more. This high temperatureprocessing served to sinter and densify the solid exterior shell andpyrolyze the wax such that the pores of the sintered body werere-opened.

Example 7 Production of a Porous Ceramic Body Exhibiting a SolidExterior Shell

A porous ceramic body with a solid exterior shell was produced byinserting a cylindrical open pore polyurethane foam precursor into asleeve of a pyrolyzable material, such as polystyrene, and immersing theentire structure into a thixotropic slurry. Excess slurry wassubsequently removed by using a vacuum and the ceramic coating givensufficient time to dry. This process was repeated until the ceramiccoating attained the desired thickness at which point the entirestructure was sintered at a temperature in excess of about 1000° C. fora period greater than about 1 hr. This high temperature processingserved to sinter the ceramic body together and pyrolyze both the openpore polyurethane foam and the polystyrene sleeve. The end result was aporous ceramic body with an exterior solid shell.

Example 8 Method for the Production of an Open Pore Ceramic Body

The excess slurry deposited during the replication technique was removedin order that the pores of an open pore polyurethane foam precursorremained open throughout the replication process during application ofmultiple coatings of a ceramic material. The method involved removingthe excess slurry by placing the slurry infiltrated foam precursor ontoa mesh screen that was either attached to a vertically mounted vacuumhose or placed across an opening in a vacuum box, and removing theslurry by turning the vacuum on for several seconds. This process couldbe enhanced by using a jet or curtain of compressed air in combinationwith the vacuum to push the excess slurry through the foam and into thevacuum hose or box. Proper design of the vacuum system enabled a largefraction of the expelled slurry to be reclaimed and reused duringsubsequent coatings.

Example 9 Method for the Production of an Open Pore Ceramic Body

An open pore ceramic body was produced using rapid prototyping (RP)techniques. In this method, an osteoconductive/osteoinductive ceramicpowder was obtained and formed into a sintered porous ceramic body usingrapid prototyping techniques such as selective laser sintering (SLS). Analternative method for producing a sintered porous ceramic body using RPtechniques was to first coat the ceramic particles with an appropriatepolymer/binder then use low temperature SLS to effectively bind theceramic particles together. Subsequent high temperature thermalprocessing served to pyrolyze the polymer/binder while sinteringtogether the ceramic particles. An additional technique used to form theporous green body was to apply a binder to a bed of ceramic powder usingink jet printer technology. The green body was subsequently processed athigh temperatures to pyrolyze the binder and sinter the ceramicparticles together. In all aspects of this example, the porous ceramicbody was manufactured by the successive build up of layers as is typicalof all rapid prototyping technologies. As the part is created from a CADmodel, the formation of components exhibiting gradient porosities, densecortical shells and varying geometries is readily achievable.

Although preferred embodiments of the present invention are described indetail herein, it will be understood by those skilled in the art thatvariations may be made thereto without departing from the spirit of theinvention.

1. A porous ceramic composite implant, said implant comprising; a porousceramic matrix having a biodegradable polymer provided on internal andexternal surfaces of said ceramic matrix, wherein said biodegradablepolymer allows for the passage and/or delivery of a variety of agentsthroughout said porous ceramic matrix and improves mechanical propertiesof said implant.
 2. The implant of claim 1, wherein said biodegradablepolymer is provided as a continuous coating.
 3. The implant of claim 1,wherein said biodegradable polymer is provided as a discontinuouscoating.
 4. The implant of any one of claims 1 to 3, wherein saidbiodegradable polymer is porous.
 5. The implant of claim 2, 3 or 4,wherein said biodegradable polymer is provided as a polymer compositefurther comprising particles of ceramic matrix.
 6. The implant of claims4 or 5, wherein said biodegradable polymer is selected from the groupconsisting of photosensitive polymers, polycaprolactone, polyanhydrides,poly(ortho esters), poly(amino acids), pseudo-poly(amino acids),polyethylene glycol, polyesters and mixtures thereof.
 7. The implant ofclaim 6, wherein said photosensitive polymers are selected frompolyhydroxybutyrate, polyhydroxyvalerate and copolymers thereof.
 8. Theimplant of claim 6, wherein said polyester is selected from poly(lacticacid) and poly(glycolic acid).
 9. The implant of claim 4 or 5, whereinsaid coating has a thickness of up to about 250 microns.
 10. The implantof claim 9, wherein said biodegradable polymer has a pharmaceuticalagent incorporated therein.
 11. The implant of claim 10, wherein saidpharmaceutical agent is an agent selected from the group consisting ofepidermal growth factor, fibroblast growth factor, platelet derivedgrowth factor, transforming growth factor, antimicrobials, antibiotics,parathyroid hormone, leukemia inhibitory factor, insulin-like growthfactor, bone morphogenetic proteins, osteogenin, sodium fluoride,estrogens, calcitonin, biphosphonates, calcium carbonate,prostaglandins, vitamin K and mixtures thereof.
 12. The implant of claim9 or 10, wherein said porous ceramic matrix is loaded with a populationof cells selected from the group consisting of cartilage cells, tendoncells, bone cells, ligament cells, organ cells, musculotendinous cellsand mixtures thereof.
 13. The implant of claim 1 or 9, wherein saidporous ceramic matrix is a compound comprising calcium, oxygen andphosphorous, wherein a portion of at least one of said elements issubstituted with an element having an ionic radius of approximately 0.1to 0.6 Å.
 14. The implant of claim 13, wherein said compound has theformula:(Ca)_(i){(P_(1-x-y-z)B_(x)C_(y)D_(z))O_(j)}₂ wherein B, C and D areselected from those elements having an ionic radius of approximately 0.1to0.4 Å; x is greater than or equal to zero but less than 1; y isgreater than or equal to zero but less than 1; z is greater than orequal to zero but less than 1; x+y+z is greater than zero but less than1; i is greater than or equal to 2 but less than or equal to 4; and j isequal 4−δ, where δ is greater than or equal to zero but less than orequal to
 1. 15. The implant of claim 4, wherein said biodegradablepolymer has a porosity of about 50 to about 200 microns.
 16. The implantof claim 1 or 4, wherein said biodegradable polymer has a substantiallyhigh degree of porosity.
 17. The implant of claim 16, wherein saidporous ceramic matrix has a porosity of about 200 to about 600 microns.18. The implant of claim 5, wherein said ceramic particles are up toabout 50 microns.
 19. The implant of claim 17, wherein said porousceramic matrix has a gradient porosity.
 20. A method of making a porousceramic implant for connective tissue replacement, said methodcomprising; (i) impregnating an organic reticulated foam structure witha slurry of calcium-phosphate compound; (ii) drying the impregnated foamstructure to form a slurry coated foam structure; and (iii) pyrolyzingthe slurry coated foam structure formed in (ii) and sintering to providea fused ceramic porous implant having a plurality of interconnectedvoids.
 21. The method of claim 20, wherein said slurry is formed bymixing a calcium phosphate compound with water and a dispersing agent.22. The method of claim 21, wherein said dispersing agent is selectedfrom the group consisting of sodium polyacrylate, ammonium polyacrylate,sodium citrate, sodium tartrate, sodium carbonate, sodium silicate,tetrasodium pyrophosphate and mixtures thereof.
 23. The method of claim22, wherein said slurry comprises about 1 to about 3.5% by volumedispersing agent.
 24. The method of claim 21, wherein said slurry ismilled to contain solid particle sizes of up to about 50 microns priorto impregnation of said foam structure.
 25. The method of claim 24,wherein one or more additives is added to said slurry.
 26. The method ofclaim 25, wherein said additive is selected from the group consisting ofbinder, wetting agent, anti-foaming agent and mixtures thereof.
 27. Themethod of claim 26, wherein said slurry comprises about less than 10% byvolume binder.
 28. The method of claim 26, wherein said slurry comprisesless than about 2% by volume wetting agent.
 29. The method of claim 26,wherein said slurry comprises less than about 2% by volume anti-foamingagent.
 30. The method of claim 20, wherein step (ii) is repeated until adesired thickness of coating of up to about 100 microns is achieved. 31.The method of claim 24, wherein said slurry has a solid content ofmilled particles of up to about 30% by volume.
 32. The method of claim20, wherein after step (i) any excess slurry is removed by vacuum. 33.The method of claim 20, wherein step (ii) is conducted at a temperatureof up to about 90° C.
 34. The method of claim 33, wherein step (iii)heating is conducted at a temperature of up to about 200° C. andsintering is conducted at a temperature of up to about 1300° C.
 35. Themethod of claim 20, wherein after step (iii) a thermally decomposablematerial is provided within interstices of the porous ceramic compositeand a slip casting process is used to coat selected surfaces of saidporous ceramic composite followed by thermal processing to provide asolid ceramic coating on said ceramic porous implant.
 36. The method ofclaim 20 or 35, wherein said calcium phosphate compound comprisescalcium, oxygen and phosphorous, wherein a portion of at least one ofsaid elements is substituted with an element having an ionic radius ofapproximately 0.1 to 0.6 Å.
 37. The method of claim 36, wherein saidcompound has the formula:(Ca)_(i){(P_(1-x-y-z)B_(x)C_(y)D_(z))O_(j)}₂ wherein B, C and D areselected from those elements having an ionic radius of approximately 0.1to 0.4 Å; x is greater than or equal to zero but less than 1; y isgreater than or equal to zero but less than 1; z is greater than orequal to zero but less than 1; x+y+z is greater than zero but less than1; i is greater than or equal to 2 but less than or equal to 4; and j isequal 4−δ, where δ is greater than or equal to zero but less than orequal to
 1. 38. The method of claim 20, wherein step (i) is conductedusing centripetal force to provide gradient porosity.
 39. The method ofclaim 20 or 35, wherein a biodegradable polymer is applied to exteriorand interior surfaces of said porous ceramic implant.
 40. The method ofclaim 39, wherein said biodegradable polymer is provided as a continuouscoating.
 41. The method of claim 40, wherein said biodegradable polymeris provided as a discontinuous coating.
 42. The method of claim 40 or41, wherein said biodegradable polymer is porous.
 43. The method ofclaim 40, 41 or 42, wherein said biodegradable polymer is provided as apolymer composite containing particles of porous ceramic matrix.
 44. Themethod of claim 41, 42 or 43, wherein said biodegradable polymer isselected from the group consisting of photosensitive polymers,polycaprolactone, polyanhydrides, poly(ortho esters), poly(amino acids),pseudo-poly(amino acids), polyethylene glycol, polyesters and mixturesthereof.
 45. The method of claim 44, wherein said photosensitivepolymers are selected from polyhydroxybutyrate, polyhydroxyvalerate andcopolymers thereof.
 46. The method of claim 44, wherein said polyesteris selected from poly(lactic acid) and poly(glycolic acid).